Local delivery of estrogen for angiogenesis

ABSTRACT

A method for inducing angiogenesis in blood vessels proximal to ischemic tissue or proximal to stenosed regions including application of an estrogen compound to the blood vessel walls at a treatment site proximal to or upstream of the stenosis. A preferred delivery device is a double walled drug delivery catheter having porous outer walls. Another suitable delivery device is a drug injection device for injecting angiogenic material into blood vessel walls. One delivery method utilizes iontophoresis.

FIELD OF THE INVENTION

The invention relates generally to a method for inducing angiogenesisupstream of blood vessel occlusions. More specifically, the inventionrelates to applying estrogen compounds to blood vessel regions to induceangiogenesis upstream of ischemic tissue.

BACKGROUND OF THE INVENTION

Arteriosclerosis and the resulting myocardial infarction is a leadingcause of death, particularly in males. Percutaneous TransluminalCoronary Angioplasty (PTCA) is one treatment used to treat patients withcoronary artery disease. PTCA can relieve myocardial ischemia bydilating lumen obstructions, thereby increasing coronary blood flow.Unfortunately, restenosis following PTCA is a significant problem,occurring about 30% of the time within 6 months. Various treatments havebeen suggested to deal with restenosis.

Administration of compounds for inhibiting vascular smooth muscle cellproliferation and restenosis has been suggested by Cullinan et al. (U.S.Pat. No. 5,462,937). Woods (U.S. Pat. No. 5,180,366) discloses anapplication of smooth muscle cell anti-proliferation agents, includingestrogen, and endothelial growth factor to inhibit restenosis has alsobeen suggested. Growth and division of endothelial cells was said to bepromoted while proliferation of smooth muscle cells was believed to beinhibited.

Application of Vascular Endothelial Growth Factor (VEGF) as apost-operative wound healing agent after balloon angioplasty has beensuggested, in an amount effective to promote endothelial cell growth byTischer et al. (U.S. Pat. No. 5,219,739). Inhibition of smooth musclecell proliferation by administration of an effective amount ofTransforming Growth Factor-beta activators or production simulators thatact to inhibit vascular smooth muscle cell proliferation has also beenproposed by Grainger et al. (U.S. Pat. No. 5,472,985).

It is believed that the more common occurence of restenosis in mencompared to women suggests hormones play a role. Oral, transdermal, andimplant delivery administration of a therapeutically effective amount ofestrogen has been suggested as a method for reducing the risk of heartdisease by Hughes et al. (U.S. Pat. No. 5,516,528). A method forreducing restenosis by administering estrogen in a dose sufficient tostimulate synthesis of 27-hydroxychloresterol in the vascularendothelium tissue has also been proposed by Javitt (U.S. Pat. No.5,376,652). Administration of estrogen to the stenosed, dilated regionafter PTCA has thus been suggested for the purposes of preventingrestenosis.

PTCA is not always a successful solution or even a viable treatmentoption, as not all stenosed regions can be treated with PTCA. Forexample, some regions are unreachable with the required size highpressure balloon, which must be advanced through the narrowed, occludedvessel region. Some stenoses are totally blocked, denying entry to adilitation catheter attempting to advance within. Other vessel regionsare too narrow or geometrically too tortuous for dilitation. Damage toweakened vessel walls is a possibility during balloon inflation as well,and may preclude PTCA in some cases. Treatment to increase perfusion toheart tissue, in place of, or in addition to, PTCA would be desirable.

SUMMARY OF THE INVENTION

The present invention provides a method for increasing circulation toheart tissue involving the application of estrogen compounds to bloodvessel walls to promote angiogenesis. Applicants believe estrogeninduces angiogenesis (blood vessel growth) and increases permeability.This provides increased local blood circulation throughneovascularization, the creation of new blood vessels.

A preferred location for application of the estrogen is proximal to, orupstream of, ischemic tissue or a stenosis. This creates new bloodvessels proximal to the ischemic tissue or a stenosis. The invention isrelatively more beneficial when practiced in smaller blood vessels whenit is considered that smaller vessels are the vessels more likely topresent difficulties in being crossed with balloon catheters anddilated, while also being the vessels which supply blood to a smallerarea of tissue which is believed benefited most from angiogenesis.

One method of delivering the angiogenesis inducing compound or estrogencompound includes application with a double walled drug delivery ballooncatheter having a porous outer wall. A preferred catheter is a perfusionballoon catheter. The balloon can be advanced to a site proximal theischemic tissue or stenosis, the inner balloon inflated, bringing theouter balloon into close contact with the blood vessel wall. Thecompound can then be injected into the catheter lumen, thereafterflowing into the space between the balloon walls, and out to contact thevessel walls.

In yet another embodiment, a balloon envelope is coated with a viscousor otherwise difficult to inject estrogen containing compound. Theballoon envelope and a sheath are advanced co-extensively until reachingthe treatment site, the sheath withdrawn, and the balloon expanded,forcing the compound against the vessel wall.

Another method of delivering the estrogen compound includes use ofiontophoresis. A delivery balloon releases the compound within thevessel, where the compound is ionic or can be carried along with anionic material. Electrodes external to the patients body are used tocreate an electric field which acts as a driving force to causemolecules to advance toward an oppositely charged pole.

Yet another method of compound delivery includes advancing a drugdelivery catheter having a puncturing element to the delivery site. Thepuncturing element is moved to puncturing position, the inner wallpunctured, and the compound injected into the vessel wall. An estrogencompound could also be coated on a stent and placed at a desireddelivery site, temporarily or permanently.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a fragmentary side elevational view of a stenosed vesselsectioned vertically on the vessel longitudinal axis and having anestrogen compound applying catheter proximally thereof; and

FIG. 2 is an enlarged sectional view of FIG. 1 taken along 2--2,illustrating estrogen compound flow from application device throughouter envelope to the vessel wall.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A preferred method of estrogen compound material delivery includesinflating a balloon having an estrogen compound covering a substantialportion of the balloon. The compound is thus held in place against thevessel wall, promoting adsorption through the vessel wall. A preferredcatheter for delivery is a perfusion balloon catheter. A catheterallowing perfusion therethrough allows holding the estrogen compoundagainst the vessel walls for longer adsorption times while allowingblood to flow through the blood vessel. Examples of catheters suitablefor estrogen compound application are drug delivery catheters asdisclosed in U.S. Pat. No. 5,558,642, entitled "Drug Delivery Catheter"or U.S. Pat. No. 5,554,119, entitled "Drug Delivery Catheter withManifold", the disclosures of which are incorporated herein byreference. Another suitable catheter is disclosed in U.S. patentapplication Ser. No. 08/441,618, filed May 15, 1995, entitled "PerfusionBalloon Angioplasty Catheter", now U.S. Pat. No. 5,591,129, to thepresent assignee, the disclosure of which is incorporated herein byreference. This disclosed catheter can be constructed with a porous drugdelivery member over the balloon, as illustrated in FIG. 1.

FIG. 1 illustrates a blood vessel 20 having an inner wall 23, a lumen 26and stenosed region 30 and a more proximal region 24, where stenosedregion 22 is more occluded and proximal region 24 is less occluded.Stenosed region 22 includes a stenosis 33 within as representative of anarea of ischemic tissue. A compound delivery device 40 is illustrated,here double walled balloon catheter 40, inserted to a treatment site invessel lumen 26 proximal to or upstream of stenosed region 22. Catheter40 has a balloon 43 extending from balloon proximal end 42 to balloondistal end 44. Balloon 43 includes an inner envelope 48 and an outer,porous envelope 46. An interior space 47 lies between inner envelope 48and outer envelope 46. The embodiment illustrated includes a proximalprotrusion 52 and a distal protrusion 50, both shown extending in closeproximity to vessel inner wall 23. Catheter 40 includes a combinationperfusion-guide wire lumen 55.

Catheter 40 is shown containing a guide wire 54 within a guide wirelumen 56. Catheter 40 also includes an inflation lumen 58 and a compoundapplication lumen 60. A preferred embodiment includes a radiopaquemarker band 62. An estrogen inducing compound 64 is illustrated withinlumen 60, within interior space 47, outside outer envelope 46, and incontact with vessel inner wall 23. Estrogen compound 64 is shown flowingbetween holes 45 in outer envelope 46 to vessel inner wall 23.

FIG. 2 illustrates in greater detail estrogen compound 64 flowing at 65through holes 45 in outer envelope 46 to vessel inner wall 23. Thecontours and spaces between the catheter balloon 43 and the vessel wall23, along with the thickness of estrogen compound 64 are not drawn toscale in FIGS. 1 and 2, but rather illustrate the application of thepresent invention.

In use, guide wire 54 can be advanced through the vasculature and justproximal to or through stenosis 30. Delivery catheter 40 may then bethreaded onto guide wire 54 and advanced to a position proximal to orupstream of stenosis 30. Once in place, inner balloon 43 can beinflated, causing outer balloon 46 to more closely approach or touchvessel wall 23. Estrogen compound 64 can then be injected into compoundlumen 60, forcing the compound into interior space 47 and through holes45 in porous outer balloon 46. A preferred method of delivery includesfurther pressurizing inner balloon 48 to force estrogen compound 64against vessel inner wall 23. Another preferred method includesinjecting compound 64 under pressure while inflation pressure is beingsupplied to balloon 48, applying estrogen compound 64 under pressureagainst vessel inner wall 23.

Preferred estrogen compounds include 17-Beta Estradiol, estradiol (E2)or estriol (E3).

Numerous characteristics and advantages of the invention covered by thisdocument have been set forth in the foregoing description. It will beunderstood, however, that this disclosure is, in many respects, onlyillustrative. Changes may be made in details, particularly in matters ofshape, size, and arrangement of parts without exceeding the scope of theinvention. The inventions's scope is, of course, defined in the languagein which the appended claims are expressed.

What is claimed is:
 1. A method for increasing blood flow to ischemictissue proximal to a constricted blood vessel region comprising the stepof inducing angiogenesis in a less constricted blood vessel regionproximal to said constricted region by applying an effective amount ofestrogen compound for causing angiogenesis to said less constrictedblood vessel region.
 2. The method of claim 1, wherein said methodfurther comprises providing an application device, wherein saidapplication device is a balloon catheter.
 3. The method of claim 1,wherein said less constricted blood vessel region has walls and saidapplying step includes depositing said compound on said walls.
 4. Themethod of claim 1, wherein said applying device is a double walledballoon catheter having a porous outer wall.
 5. The method of claim 4,wherein said catheter includes a perfusion lumen.
 6. The method of claim1, wherein said less constricted blood vessel region has walls, saidapplication device is an injection device, and said applying stepincludes injecting said compound into said walls.
 7. The method of claim1, wherein said estrogen compound is selected from the group consistingof estradiol(E2) and estriol(E3).
 8. The method of claim 1, wherein saidestrogen compound is 17-Beta Estrodiol.
 9. The method of claim 1,wherein said less constricted blood vessel region has walls, and saidmethod includes providing an application device including aniontophoresis device and said applying step includes depositing saidcompound on said walls and transporting said compound through said wallsutilizing said iontophoresis device.